WO2017140253A1 - 一种含有咪唑啉类衍生物的药物组合物 - Google Patents

一种含有咪唑啉类衍生物的药物组合物 Download PDF

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WO2017140253A1
WO2017140253A1 PCT/CN2017/073868 CN2017073868W WO2017140253A1 WO 2017140253 A1 WO2017140253 A1 WO 2017140253A1 CN 2017073868 W CN2017073868 W CN 2017073868W WO 2017140253 A1 WO2017140253 A1 WO 2017140253A1
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Prior art keywords
pharmaceutical composition
composition according
cellulose
hydroxypropylcellulose
filler
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PCT/CN2017/073868
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English (en)
French (fr)
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卢韵
张新华
张代美
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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Priority to HK18104328.5A priority Critical patent/HK1244703B/zh
Priority to CA3014088A priority patent/CA3014088A1/en
Priority to KR1020187025162A priority patent/KR20180109991A/ko
Priority to AU2017220970A priority patent/AU2017220970B2/en
Priority to CN201780001360.5A priority patent/CN107530325B/zh
Priority to US16/077,610 priority patent/US10588978B2/en
Priority to MX2018009742A priority patent/MX377657B/es
Priority to JP2018537445A priority patent/JP6968075B2/ja
Priority to EP17752685.2A priority patent/EP3417857B1/en
Priority to RU2018129762A priority patent/RU2749135C2/ru
Priority to BR112018015370-2A priority patent/BR112018015370A2/zh
Publication of WO2017140253A1 publication Critical patent/WO2017140253A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of pharmaceutical preparations, in particular to a method comprising (S)-4-(3-(4-(2,3-dihydroxypropyloxy)phenyl)-4,4-dimethyl-5-carbonyl A pharmaceutical composition of 2-thioimidazolin-1-yl)-2-(trifluoromethyl)benzonitrile.
  • Prostate cancer is a malignant tumor that occurs in male prostate tissue and is the result of abnormal disordered growth of prostate acinar cells.
  • the differentiation and growth of normal prostate epithelial cells and the development of prostate cancer depend on androgen.
  • Male hormones are mainly synthesized in the testis, accounting for about 80-90%.
  • the synthetic androgen enters the cell and binds to the Androgen receptor (AR), causing heat shock protein (HSP) to dissociate from the AR and allow AR to enter the nucleus, activating multiple downstream genes, including prostate specific antigen (PSA).
  • AR Androgen receptor
  • HSP heat shock protein
  • PSA prostate specific antigen
  • Early prostate cancer is sensitive to androgen, and orchiectomy (castration) can significantly inhibit the development of prostate cancer. However, castration surgery has a certain timeliness.
  • the first generation drugs for the purpose of inhibiting AR activity are bicalutamide or Casodec and Flutamide.
  • the second generation of AR antagonist drugs for AlPC treatment are MDV3100 and ARN-509.
  • MDV3100 is the world's first second-generation non-steroidal AR antagonist drug, which was approved by the US FDA at the end of August 2012.
  • MDV-3100 has an affinity for AR that is 5-8 times higher than that of bicalutamide, and can inhibit the growth of AlPC mouse and human tumors by inhibiting AR activity, and does not have the effect of promoting tumor cell growth.
  • WO2014036897A1 discloses a new class of AR antagonists comprising a compound of formula (I) having the chemical name (S)-4-(3-(4-(2,3-dihydroxypropoxy)phenyl) -4,4-Dimethyl-5-carbonyl-2-thioimidazolin-1-yl)-2-(trifluoromethyl)benzonitrile, the compound is slightly better in vitro than MDV-3100, hERG The inhibition rate was further improved (IC50: 24.83uM), and the inhibitory half-lives of the five major subtypes of CYP450 were greater than 50uM. The same dose, the same dose of the drug in rats was equivalent to MDV-3100, and the in vivo exposure of canine drugs.
  • the compound of formula (I) has only one chiral center, and its chiral material is simple and easy to obtain. The difficulty of synthesis is greatly reduced.
  • the compound of formula (I) has no AR agonistic activity at 3uM and 10uM, and the ratio of drug concentration to plasma concentration in mouse brain tissue is much lower than that of MDV-3100 compound, and the possibility of epileptic side effects is smaller, so (I) Compounds have broad clinical prospects.
  • the pharmaceutical composition provided by the invention comprises an active pharmaceutical ingredient and a cellulose ether, and the active pharmaceutical ingredient is (S)-4-(3-(4-(2,3-dihydroxypropyloxy)phenyl)-4,4. -Dimethyl-5-carbonyl-2-thioimidazolin-1-yl)-2-(trifluoromethyl)benzonitrile.
  • the content of the active pharmaceutical ingredient is from 5% to 50%, preferably from 10% to 25%, based on the total weight of the pharmaceutical composition.
  • the cellulose ether described therein may be selected from one or more of alkyl cellulose, hydroxyalkyl cellulose and hydroxyalkyl alkyl cellulose, preferably hydroxyalkyl cellulose.
  • the hydroxyalkyl cellulose is selected from one or more of hydroxyethyl cellulose and hydroxypropyl cellulose, preferably hydroxypropyl cellulose, more preferably hydroxypropyl cellulose SSL and SL.
  • the hydroxyalkylalkylcellulose is selected from one or more of hydroxyethylmethylcellulose and hydroxypropylmethylcellulose.
  • the content of the cellulose ether is not particularly limited, and in a preferred embodiment, it is from 0.5% to 50%, preferably from 0.5% to 15%, most preferably from 0.5% to 10%, based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition of the present invention contains hydroxypropylcellulose, which can significantly improve the compatibility with the active pharmaceutical ingredient while improving the dissolution and bioavailability of the drug.
  • the pharmaceutical composition provided by the present invention may contain a filler, and the filler may be selected from one or more of lactose, mannitol, microcrystalline cellulose, and pregelatinized starch.
  • the filler is present in an amount of from 30% to 95%, based on the total weight of the pharmaceutical composition.
  • the filler used is lactose and microcrystalline cellulose in a total amount of from 40 to 80%, preferably from 60 to 75%.
  • the pharmaceutical composition provided by the present invention may contain a filler, and the disintegrating agent may be selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and crospovidone. One or more of them.
  • the content of the disintegrant is from 3% to 20% based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition provided by the present invention may contain a filler which may be selected from one or more of magnesium stearate, stearic acid, and glyceryl behenate. Based on the total weight of the pharmaceutical composition, The lubricant is present in an amount of from 0.1 to 2%.
  • the invention provides a pharmaceutical composition comprising the following ingredients by weight:
  • a disintegrant selected from one or more of croscarmellose sodium and sodium carboxymethyl starch;
  • a lubricant selected from one or more of magnesium stearate, stearic acid, and glyceryl behenate.
  • compositions of the present invention can be prepared by methods conventional in the art, such as high shear wet granulation, dry granulation, one-step granulation, and the like, to prepare granules of the pharmaceutical composition, which are then compressed into tablets or filled capsules.
  • the pharmaceutical composition provided by the present invention has improved stability due to the inclusion of a cellulose ether such as hydroxypropylcellulose.
  • the composition of the present invention was tested to have an increase in related substances of no more than 0.3%, preferably no more than 0.2%, more preferably no more than 0.1, and most preferably no more than 0.05% at 4 weeks under 60 °C closed conditions.
  • the composition of the present invention is completely dissolved, according to the Chinese Pharmacopoeia 2015 edition two appendix dissolution determination second method (paddle method), with 0.5% sodium dodecyl sulfate (SDS) aqueous solution, preferably 1000ml
  • SDS sodium dodecyl sulfate
  • the medium was dissolved, and the composition of the present invention was subjected to a dissolution test at a paddle speed of 50 rpm at 37 ⁇ 0.5 ° C, and the dissolution rate was 95% or more at 45 minutes or 60 minutes.
  • Compound A lactose or mannitol, microcrystalline cellulose, croscarmellose sodium, according to the ratio in Table 1, using high-speed shear
  • the granulator is subjected to wet granulation, and a 5% aqueous solution prepared from polyvinylpyrrolidone K30 is used as a binder.
  • the wet and soft materials are wet granulated and dried, and then the dry granules (water content less than 3%) are dried. Add the prescribed amount of magnesium stearate and mix well. The resulting total mixed granules were compressed into tablets.
  • the dissolution rates of the tablets of Examples 1 to 4 were measured according to the second method (paddle method) of the dissolution test of the four appendices of the Chinese Pharmacopoeia 2015 edition. 1000 ml of a 0.5% sodium dodecyl sulfate (SDS) aqueous solution was used as a dissolution medium, and a dissolution test was carried out at 37 ⁇ 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Examples 1 to 4, the compound A was completely eluted. The dissolution results are shown in Table 2.
  • SDS sodium dodecyl sulfate
  • Compound A lactose, microcrystalline cellulose, croscarmellose sodium, according to the ratio in Table 3, using a high-speed shear granulator
  • Wet granulation is carried out by using polyvinylpyrrolidone K30 as an aqueous solution, an aqueous solution prepared from pregelatinized starch, and an aqueous solution prepared by hydroxypropylcellulose SSL as a binder to wet-wet and dry the wet material. Then, the dry granules (water content less than 3%) are dry granulated, and the prescribed amount of magnesium stearate is added and uniformly mixed. The resulting total mixed granules were compressed into tablets.
  • the dissolution rates of the tablets of Examples 2, 5 and 6 were determined according to the second method (paddle method) of the dissolution test of the four appendices of the Chinese Pharmacopoeia 2015 edition. 1000 ml of a 0.5% sodium dodecyl sulfate (SDS) aqueous solution was used as a dissolution medium, and a dissolution test was carried out at 37 ⁇ 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Example 5, the dissolution of Compound A was incomplete; in Example 6, the dissolution of Compound A was complete. The dissolution results are shown in Table 4.
  • SDS sodium dodecyl sulfate
  • (S)-4-(3-(4-(2,3-Dihydroxypropyloxy)phenyl)-4,4-dimethyl-5-carbonyl-2-thioimidazolin-1-yl -2-(trifluoromethyl)benzonitrile hereinafter referred to as Compound A
  • lactose lactose
  • microcrystalline cellulose croscarmellose sodium or sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose
  • croscarmellose sodium or sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose According to the ratio in Table 5, the wet granulation was carried out by a high-speed shear granulator, and the aqueous solution prepared by using hydroxypropyl cellulose SSL was used as a binder, and the wet soft material was wet-granulated and dried, and then dried.
  • the granules water content less than 3%) are dry granules, and the prescribed amount of
  • the dissolution rates of the tablets of Examples 6 to 8 were determined according to the second method (paddle method) of the dissolution test of the four appendices of the Chinese Pharmacopoeia 2015 edition. 1000 ml of a 0.5% sodium dodecyl sulfate (SDS) aqueous solution was used as a dissolution medium, and a dissolution test was carried out at 37 ⁇ 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Example 6 and Example 7, Compound A was completely dissolved; in Example 8, Compound A was slightly incompletely dissolved. The dissolution results are shown in Table 6.
  • SDS sodium dodecyl sulfate

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Abstract

本发明提供了一种含有咪唑啉类衍生物的药物组合物。具体而言，本发明提供的药物组合物包含(S)-4-(3-(4-(2,3-二羟基丙氧基)苯基)-4,4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈和纤维素醚，该组合物具有良好的稳定性、溶出度和生物利用度。

Description

一种含有咪唑啉类衍生物的药物组合物 技术领域
本发明属于药物制剂领域，具体涉及一种含有(S)-4-(3-(4-(2,3-二羟基丙氧基)苯基)-4,4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈的药物组合物。
背景技术
前列腺癌(prostate cancer，PCa)是发生于男性前列腺组织中的恶性肿瘤，是前列腺腺泡细胞异常无序生长的结果。正常前列腺上皮细胞的分化与生长以及前列腺癌的发展依赖于雄性激素，雄性激素主要在睾丸中被合成，大约占80～90％。合成的雄性激素进入细胞后结合雄性激素受体(Androgen receptor，AR)，引起热休克蛋白(HSP)从AR上解离并使AR进入细胞核，激活多个下游基因，包括前列腺特异抗原(PSA)。早期的前列腺癌对雄性激素敏感，施行睾丸切除术(去势)能够明显抑制前列腺癌的发展。但是去势手术具有一定的时效性，许多患者经过去势后一段时间经历了从雄性激素依赖性到雄性激素非依赖性的转变，对于抗雄性激素治疗不再有效，发展为雄激素非依赖性前列腺癌(androgen independent prostate cancer，AIPC)，而AlPC的发生仍与PCa细胞内AR信号通路的活化有重要关系。
以抑制AR活性为目的的第一代药物有比卡鲁胺(Bicalutamide或Casodex)和氟他胺(Flutamide)。针对AlPC治疗的第二代AR拮抗剂药物有MDV3100和ARN-509。MDV3100是世界上首个第二代非固醇类AR拮抗剂药物，已于2012年8月底被美国FDA批准上市。MDV-3100对AR的亲和力比比卡鲁胺高5～8倍，能够通过抑制AR活性从而抑制AlPC小鼠和人肿瘤的生长，并且不具有促进肿瘤细胞生长的作用。
Figure PCTCN2017073868-appb-000001
WO2014036897A1公开了一类新的AR拮抗剂，其中包括式(I)所示化合物，其化学名为(S)-4-(3-(4-(2,3-二羟基丙氧基)苯基)-4,4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈，该化合物体外活性略优于MDV-3100，hERG抑制率进一步改善(IC50：24.83uM)，对CYP450五个主要亚型的抑制半衰期均大于50uM，同剂量，同溶媒下大鼠药代体内暴露量与MDV-3100相当，犬药代体内暴露量达MDV-3100的六倍以上。式(I)化合物仅有一个手性中心，其手性原料简单易得， 合成难度大大降低。另外，式(I)化合物在3uM和10uM均没有AR激动活性，且在小鼠脑组织中药物浓度与血药浓度比值远低于MDV-3100化合物，出现癫痫副作用的可能性更小，因此式(I)化合物具有广阔的临床前景。
Figure PCTCN2017073868-appb-000002
然而上述文献均没有公开如何获得稳定，且溶出满足要求的含有上述化合物的药物组合物，研究发现，上述化合物稳定性较差，一些常规处方无法保证组合物的稳定性；同时，在多种常规辅制成的组合物中溶出不佳。因此，需要深入研究，发现其稳定的组合物，并且溶出良好。
发明内容
本发明的目的在于提供一种稳定性良好同时溶出迅速的药物组合物，并且该药物组合物制备工艺简单，更适合工艺化大生产。
本发明提供的药物组合物包括活性药物成分和纤维素醚，活性药物成分为(S)-4-(3-(4-(2,3-二羟基丙氧基)苯基)-4,4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈。所述活性药物成分的含量基于药物组合物的总重量计为5％-50％，可优选为10％-25％。
其中所述的纤维素醚可以选自烷基纤维素、羟烷基纤维素和羟烷基烷基纤维素中的一种或多种，优选羟烷基纤维素。羟烷基纤维素选自羟乙基纤维素和羟丙基纤维素中的一种或几种，优选为羟丙基纤维素，更优选羟丙基纤维素SSL和SL。羟烷基烷基纤维素选自羟乙基甲基纤维素和羟丙基甲基纤维素中的一种或几种。
纤维素醚的含量没有特别限制，在优选的实施方案中，基于药物组合物的总重量计为0.5％-50％，优选为0.5％-15％，最优为0.5％-10％。
在特别优选的实施方案中，本发明的药物组合物中含有羟丙基纤维素，可以显著改善与活性药物成分的相容性，同时提高药物的溶出度和生物利用度。
本发明提供的药物组合物中可以含有填充剂，填充剂可以选自乳糖、甘露醇、微晶纤维素及预胶化淀粉中的一种或几种。基于药物组合物的总重量计，所述填充剂的含量为30％-95％。在本发明的一个实施例中，所用填充剂为乳糖和微晶纤维素，二者合计用量为40-80％，优选60-75％。
本发明提供的药物组合物中可以含有填充剂，所述的崩解剂可以选自交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素及交联聚维酮中的一种或多种。基于药物组合物的总重量计所述崩解剂的含量为3％-20％。
本发明提供的药物组合物中的可以含有填充剂，所述润滑剂可以选自硬脂酸镁、硬脂酸、山嵛酸甘油酯中的一种或几种。基于药物组合物的总重量计，所述 润滑剂的含量为0.1-2％。
在最为优选的实施方案中，本发明提供了一种药物组合物，含有以重量计的如下成分：
1)5％-50％的(S)-4-(3-(4-(2,3-二羟基丙氧基)苯基)-4,4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈；
2)0.5％-10％的羟丙基纤维素；
3)40-80％的填充剂，所述填充剂为乳糖和微晶纤维素的混合物；
4)3％-20％的崩解剂，所述崩解剂选自交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或几种；
5)0.1-2％的润滑剂，所述润滑剂选自硬脂酸镁、硬脂酸、山嵛酸甘油酯中的一种或几种。
本发明的药物组合物可以采用本领域常见的方法制备，例如高剪切湿法制粒、干法制粒、一步制粒等方法制备药物组合物颗粒，然后压制成片剂或者灌装胶囊。
本发明提供的药物组合物由于含有纤维素醚，如羟丙基纤维素，提高了其稳定性。经过测试，本发明的组合物置于60℃闭口条件下4周有关物质增加不超过0.3％，优选不超过0.2％，更优选不超过0.1，最优选不超过0.05％。
另一方面，本发明的组合物溶出十分完全，根据中国药典2015版二部附录溶出度测定第二法(桨法)，以0.5％的十二烷基硫酸钠(SDS)水溶液，优选1000ml为溶出介质，并在37±0.5℃下以50rpm的桨速对本发明组合物进行溶出试验，在45分钟或60分钟溶出度大于等于95％。
具体实施方式
通过以下实施例和实验例进一步详细说明本发明。这些实施例和实验例仅用于说明性目的，而并不用于限制本发明的范围。
实施例1至4
将(S)-4-(3-(4-(2,3-二羟基丙氧基)苯基)-4,4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈(以下简称化合物A)、乳糖或甘露醇、微晶纤维素、交联羧甲基纤维素钠、按照表1中的比例，采用高速剪切制粒机进行湿法制粒，以聚乙烯吡咯烷酮K30配制成的5％的水溶液为粘合剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于3％)进行干整粒，加入处方量的硬脂酸镁，混合均匀。将得到的总混颗粒压制成片剂。
表1
Figure PCTCN2017073868-appb-000003
Figure PCTCN2017073868-appb-000004
实验例1：溶出实验
根据中国药典2015版四部附录溶出度测定第二法(桨法)，对实施例1～4的片剂进行溶出度测定。以0.5％的十二烷基硫酸钠(SDS)水溶液1000ml为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实施例1～4中，化合物A溶出完全。溶出结果见表2。
表2
Figure PCTCN2017073868-appb-000005
实施例5至6
将(S)-4-(3-(4-(2,3-二羟基丙氧基)苯基)-4,4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈(以下简称化合物A)、乳糖、微晶纤维素、交联羧甲基纤维素钠、按照表3中的比例，采用高速剪切制粒机进行湿法制粒，分别以聚乙烯吡咯烷酮K30配制成水溶液、预胶化淀粉配制成的水溶液以及羟丙基纤维素SSL配制成的水溶液作为粘合剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于3％)进行干整粒，加入处方量的硬脂酸镁，混合均匀。将得到的总混颗粒压制成片剂。
表3
Figure PCTCN2017073868-appb-000006
Figure PCTCN2017073868-appb-000007
实验例2：溶出实验
根据中国药典2015版四部附录溶出度测定第二法(桨法)，对实施例2、5、6的片剂进行溶出度测定。以0.5％的十二烷基硫酸钠(SDS)水溶液1000ml为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实施例5中，化合物A溶出不完全；实施例6中，化合物A溶出完全。溶出结果见表4。
表4
Figure PCTCN2017073868-appb-000008
实施例7至8
将(S)-4-(3-(4-(2,3-二羟基丙氧基)苯基)-4,4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈(以下简称化合物A)、乳糖、微晶纤维素、交联羧甲基纤维素钠或羧甲基淀粉钠或低取代羟丙基纤维素，按照表5中的比例，采用高速剪切制粒机进行湿法制粒，以羟丙基纤维素SSL配制成的水溶液作为粘合剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于3％)进行干整粒，加入处方量的硬脂酸镁，混合均匀。将得到的总混颗粒压制成片剂。
表5
Figure PCTCN2017073868-appb-000009
Figure PCTCN2017073868-appb-000010
实验例3：溶出实验
根据中国药典2015版四部附录溶出度测定第二法(桨法)，对实施例6～8的片剂进行溶出度测定。以0.5％的十二烷基硫酸钠(SDS)水溶液1000ml为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实施例6和实施例7中，化合物A溶出完全；实施例8中化合物A溶出稍不完全。溶出结果见表6。
表6
Figure PCTCN2017073868-appb-000011
实验例4：相容性研究
使用聚维酮类作为粘合剂时，通过辅料的相容性研究发现有关物质会明显增加，提示聚维酮类和药物的相容性不佳，但使用羟丙基纤维素时则稳定性良好。
表7
Figure PCTCN2017073868-appb-000012

Claims (11)

  1. 一种药物组合物，含有作为活性成分的(S)-4-(3-(4-(2,3-二羟基丙氧基)苯基)-4,4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈以及纤维素醚。
  2. 根据权利要求1所述的药物组合物，其中所述的纤维素醚选自烷基纤维素、羟烷基纤维素和羟烷基烷基纤维素中的一种或多种，优选羟烷基纤维素。
  3. 根据权利要求2所述的药物组合物，其中所述的羟烷基纤维素选自羟乙基纤维素和羟丙基纤维素中的一种或几种，优选为羟丙基纤维素，更优选羟丙基纤维素SSL和SL。
  4. 根据权利要求2所述的药物组合物，其中所述的羟烷基烷基纤维素选自羟乙基甲基纤维素和羟丙基甲基纤维素中的一种或几种。
  5. 根据权利要求1-4中任一项所述的药物组合物，其中所述纤维素醚基于药物组合物的总重量计0.5％-50％，优选为0.5％-15％，最优为0.5％-10％。
  6. 根据权利要求1-4中任一项所述的药物组合物，其特征在于还含有填充剂，所述填充剂选自乳糖、甘露醇、微晶纤维素及预胶化淀粉中的一种或几种；优选乳糖和微晶纤维素中的一种或几种。
  7. 根据权利要求1-4中任一项所述的药物组合物，其特征在于还含有崩解剂，其中所述的崩解剂为交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素及交联聚维酮中的一种或几种；优选交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或几种。
  8. 根据权利要求1-4中任一项所述药物组合物，其特征在于还含有润滑剂，所述润滑剂为硬脂酸镁、硬脂酸、山嵛酸甘油酯中的一种或几种。
  9. 一种药物组合物，含有以重量计的如下成分：
    1)5％-50％的(S)-4-(3-(4-(2,3-二羟基丙氧基)苯基)-4,4-二甲基-5-羰基-2-硫代咪唑啉-1-基)-2-(三氟甲基)苯甲腈；
    2)0.5％-10％的羟丙基纤维素；
    3)40-80％的填充剂，所述填充剂为乳糖和微晶纤维素的混合物；
    4)3％-20％的崩解剂，所述崩解剂选自交联羧甲基纤维素钠、羧甲基淀粉钠中的一种或几种；
    5)0.1-2％的润滑剂，所述润滑剂选自硬脂酸镁、硬脂酸、山嵛酸甘油酯中的一种或几种。
  10. 权利要求1至9任一项所述的药物组合物的制备方法，所述方法包括混合高剪切制粒、流化床一步制粒或直接压片的步骤，任选地包括混合制粒后压片或填装胶囊的步骤。
  11. 权利要求1至9任一项所述药物组合物在制备治疗和预防前列腺癌的药物中的用途。
PCT/CN2017/073868 2016-02-19 2017-02-17 一种含有咪唑啉类衍生物的药物组合物 Ceased WO2017140253A1 (zh)

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